TABLE 2.
| Gene | Human Disease/Animal Model | Potential Translational Application |
|---|---|---|
| Hdac1/2 | Hdac2 promotes cardiac hypertrophy [110]; Hdac1/2 combined deficiency in T cells leads to neoplastic transformation [103]; acute ischemic injury and organ fibrosis reduced by Hdac inhibition [111, 112]. | Broad spectrum (e.g. TSA) and Hdac class1 specific (aminobenzamides) inhibitors [113]; valproic acid (epilepsy); two FDA approved drugs for cutaneous T cell lymphoma (Vorinostat, Romidepsin) [114]; phase 3 clinical trials in progress for other malignancies1; expansion of cord blood stem cells [115] |
| Chd3/4/5 | Mi2β auto-antibody diagnostic marker of dermatomyositis; frequent mutations of CHD4 in serous endometrial cancer [79, 80]; deletion of Chd4 in mice leads to erythroid leukemia [60]. CHD4 implicated in glioblastoma [94] CHD5 deletion and promoter methylation in CNS and other tumors [95] | Silencing of Mi2-NuRD to increase fetal Hgb as treatment of hemoglobinopathies (e.g thalassemia) [42]; calixarene-based supramolecular hosts prevent binding of CHD4 PHD2 to H3Kme3 [116]. |
| Mbd2/3 | Frequent chromosomal deletion encompassing MBD3 in serous endometrial cancer[80]; Mbd2 deficiency in mice suppresses intestinal tumor formation [117]. | Mbd3 inhibition for efficient generation of iPS cells [57, 58]; DNA methylation inhibitors to modulate Mbd2-dependent gene silencing (cancer, thalassemia) [26]; disrupt interaction with p66 (see Gata 2a/2b column below) |
| Mta1/2/3 | Increases in expression of MTAs correlate with increased metastases and poor outcome in a large variety of tumors [118]. Mta1-3 modulate pathways in breast cancer (Estrogen Receptor, Wnt, EMT); CNVs overlapping MTA3 in Li-Fraumeni syndrome with brain tumors [119]; Mta2 mouse mutant with systemic lupus-like features [108] | Potentially attractive targets for cancer and inflammatory diseases. No structures available to guide drug design; potential need for selectivity for specific MTAs. |
| Rbbp4/7 | Probable role in disease processes through its interactions with multiple cellular proteins, though specific role in pathogenesis not clearly defined2. | Structure based drug design possible but given broad/promiscuous range of protein interactions may have significant toxicity. |
| Gata2a/2b | GATA2b loss-of-function and truncating mutations associated with autosomal dominant intellectual impairment and dysmorphic facial features [69, 74] | Inhibition of Gata 2a/2b colied-coil interaction with Mbd2/3 with peptide or small molecule to disrupt NuRD [27] |
2
Databases searched for human disease/animal model include PubMed (www.ncbi.nlm.nih.gov/pubmed), Mouse Genome Informatics (MGI, www.informatics.jax.org), Gene Cards (www.genecards.org), and Online Mendelian Inheritance in Man (OMIM, www.ncbi.nlm.nih.gov/omim).